Despite recent advances in antiviral therapy, there is no permanent cure for AIDS or HIV infection. Drug therapy, is a promising arena of investigation in terms of providing effective therapy, however because of side effects, compliance, and expense, progress has not been rapid. Compounding these difficulties is the fact that the availability of such drugs is limited in developing countries where it is estimated that the vast majority of new HIV infections will occur.
Due to the success that vaccines to infectious diseases have had, the most notable being against small pox and polio, the search for an effective vaccine against AIDS continues. A variety of approaches have been tried. Indeed, most HIV-1 vaccine development has concentrated on subunit vaccines. The difficulty with the subunit vaccine approach has been the ability to produce optimal immunity. At present, it is not known exactly which components of the HIV antigen(s) and the immune system are necessary for protection from natural infection.
The preferred route for developing vaccines in general is to use whole, inactivated or attenuated viruses, such as the inactivated polio virus vaccine, or attenuated live virus vaccines, such as oral polio vaccine. Unfortunately, this approach can be problematic as shown by the “Cutter incident” in which inadequate inactivation of the polio vaccine resulted in vaccine-mediated transmission of clinical polio.
Early vaccine trials have looked at recombinant subunit protein based immunogens, such as the HIV-1 envelope glycoprotein 120 (gp120). The majority of results from this approach have been disappointing, although immunization regimens that employ both live recombinant virus and subunit protein have, in some individuals, elicited both envelope specific CD8+CTL and neutralizing antibody to the HIV-1 envelope (Cooney, E. L. et al. Proc. Natl. Acad. Sci. USA 90: 1882-86 (1993); McElrath, M. J. et al. J. Infect. Dis. 169: 41-47 (1994); Graham, B. S. et al. J. Infect. Dis. 166: 244-52 (1992); and Graham, B. S. et al. J. Infect. Dis. 167: 533-37 (1993)).
Interestingly, the signal sequence of HIV-1 gp120, which is referred to as the NSS (natural signal sequence), has been found to be associated with the extent of secretion of gp120. It has been shown that substitution of the NSS with either the honey bee mellitin or murine interlukin-3 (IL-3) signal sequence renders a high level production and efficient secretion of gp120 (Li, Y. et al. Virology 204: 266-278 (1994); and Li, Y. et al. Proc. Natl. Acad. Sci. 93: 9606-9611 (1996)). However, it is not known whether the signal sequence of HIV-1 gp120 has a role to play in the pathogenicity of the virus.
With respect to HIV vaccines, it has been shown that deletion of the HIV nef gene attenuates the virus. Desrosiers and his associates have demonstrated that vaccination of Rhesus macaques with nef deleted SIV protected wild-type SIV challenge (Daniels, M. D. et al. Science 258: 1938 (1992); Desrosiers, R. C. et al. Proc. Natl. Acad. Sci. USA 86: 6353 (1989)) and others have demonstrated that the nef gene is dispensable for SIV and HIV replication (Daniels, M. D. et al. Science 258: 1938 (1992); Gibbs, J. S., et al. AIDS Res. and Human Retroviruses 10: 343 (1994); Igarashi, T. et al. J. Gen. Virol. 78: 985 (1997); Kestler III, H. W. et al. Cell 65: 651 (1991)). Furthermore, deletion of the nef gene has been found to render the virus non-pathogenic in the normally susceptible host (Daniels, M. D. et al. Science 258: 1938 (1992)). This deletion, however, has not been found to provide a form of the virus which can be produced in large quantities.
Consequently, a vaccine which is avirulent and can be produced in large quantities is needed.